A comprehensive structural, biochemical and biological profiling of the human NUDIX hydrolase family

• The NUDIX enzymes are involved in cellular metabolism and homeostasis, as well as mRNA processing. Although highly conserved throughout all organisms, their biological roles and biochemical redundancies remain largely unclear. To address this, we globally resolve their individual properties and inter-relationships. We purify 18 of the human NUDIX proteins and screen 52 substrates, providing a substrate redundancy map. Using crystal structures, we generate sequence alignment analyses revealing four major structural classes. To a certain extent, their substrate preference redundancies correlate with structural classes, thus linking structure and activity relationships. To elucidate interdependence among the NUDIX hydrolases, we pairwise deplete them generating an epistatic interaction map, evaluate cell cycle perturbations upon knockdown in normal and cancer cells, and analyse their protein and mRNA expression in normal and cancer tissues. Using a novel FUSION algorithm, we integrate all data creating a comprehensive NUDIX enzyme profile map, which will prove fundamental to understanding their biological functionality.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology -- Medical Biotechnology (hsv//eng)

NATURVETENSKAP  -- Biologi -- Biokemi och molekylärbiologi (hsv//swe)

NATURAL SCIENCES  -- Biological Sciences -- Biochemistry and Molecular Biology (hsv//eng)

NATURVETENSKAP  -- Data- och informationsvetenskap -- Bioinformatik (hsv//swe)

NATURAL SCIENCES  -- Computer and Information Sciences -- Bioinformatics (hsv//eng)

Nyckelord

Nudix hydrolase

NUDT1 protein

NUDT10 protein

NUDT11 protein

NUDT12 protein

NUDT13 protein

NUDT14 protein

NUDT16 protein

NUDT17 protein

NUDT19 protein

NUDT20 protein

NUDT21 protein

NUDT22 protein

NUDT4 protein

NUDT5 protein

NUDT6 protein

NUDT7 protein

NUDT8 protein

unclassified drug

algorithm

biochemical composition

cancer

enzyme

enzyme activity

gene expression

homeostasis

metabolism

protein

A-549 cell line

Article

breast cancer

cancer cell line

cancer tissue

cell cycle

cell cycle regulation

cell survival

colorectal cancer

controlled study

DNA content

enzyme structure

functional genomics

gene interaction

gene silencing

human

human cell

human tissue

immunohistochemistry

melanoma

phylogenetic tree

protein expression

sequence alignment

tissue microarray

upregulation

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)